IL-9-dependent interstitial macrophage function in the allergic lung

过敏性肺中 IL-9 依赖性间质巨噬细胞功能

• 批准号: 10741356
• 负责人: MARK H KAPLAN
• 金额: $ 46.11万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10741356
• 关键词: Abbreviations; Adoptive Transfer; Affect; Allergens; Allergic; Allergic Disease; Allergic inflammation; Alveolar Macrophages; Arginine; Asthma; Attenuated; Binding; Cells; Chronic Disease; Cost of Illness; Data; Data Set; Dendritic Cells; Development; Disease; Environment; Enzymes; Funding; Gene Expression; Gene Expression Regulation; Generations; Genes; Goals; Grant; Health; Health Care Costs; Heterogeneity; High-Throughput Nucleotide Sequencing; ITGAX gene; Immune; Inflammation; Inflammatory; Interleukin-2; Interleukin-9; Lung; Lymphoid Cell; Macrophage; Mediating; Metabolic; Metabolic Pathway; Mucous Membrane; Mus; Mutant Strains Mice; Organ; Pathway interactions; Phenotype; Polyamines; Population; Process; Productivity; Pyroglyphidae; Regulation; Signal Transduction; Small Interfering RNA; Sorting; T-Lymphocyte; Therapeutic; United States; Work; allergic airway inflammation; allergic response; arginase; asthmatic patient; autocrine; cell type; conditional mutant; cytokine; in vivo; interstitial; mast cell; monocyte; nanoparticle; novel; pulmonary function; recruit; response; single-cell RNA sequencing; therapeutic target; transcription factor

PROJECT SUMMARY / ABSTRACT: IL-9-dependent interstitial macrophage function in the allergic lung Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9 responsive cell repertoire is still not well defined. In a thorough study to identify IL-9-responsive cells, we found that IL-9 mediates pro-allergic activities by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c+/- interstitial macrophage populations. Interstitial macrophages are required for IL-9-dependent allergic responses. Mechanistically, IL-9 affects the function of lung macrophages by inducing Arg1 activity. Adoptive transfer of Arg1+ lung macrophages but not Arg1- lung macrophages can recover allergic inflammation that is lost in Il9r-/- mice. In parallel, the elevated expression of IL-9, IL-9R, and Arg1 is correlated with disease in asthma patients. Thus, our studies uncover an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation. In this renewal application we will leverage single cell RNA-seq datasets to further define the interstitial macrophage population that displays pro-allergic function. We will determine the IL-9-dependent pathways that lead to changes in macrophage gene expression. Finally, we will determine how Arg1-dependent metabolic pathways impact intrinsic gene expression in macrophages. Together, these studies will establish a detailed understanding of macrophage function in the allergic lung and identify pathways that can be explored for therapeutic value.

项目总结/摘要：过敏性肺中的IL-9依赖性间质巨噬细胞功能 尽管IL-9在粘膜环境中起多效性细胞因子的作用，但IL-9应答细胞库是 还没有很好的定义。在一项鉴定IL-9应答细胞的全面研究中，我们发现IL-9介导促过敏反应， 活性靶向肺巨噬细胞。IL-9抑制肺泡巨噬细胞扩张并促进募集 单核细胞发育成CD 11 c +/-间质巨噬细胞群。间质巨噬细胞 这是IL-9依赖性过敏反应所必需的。IL-9影响肺巨噬细胞的功能 通过诱导Arg 1活性。Arg 1+肺巨噬细胞而非Arg 1-肺巨噬细胞的连续转移可 恢复在Il 9 r-/-小鼠中丢失的过敏性炎症。与此同时，IL-9、IL-9 R和IL-10的表达升高， Arg 1与哮喘患者的疾病相关。因此，我们的研究揭示了IL-9/巨噬细胞/Arg 1轴， 过敏性气道炎症的潜在治疗靶点。在此更新应用程序中，我们将利用单个 细胞RNA-seq数据集，以进一步定义显示促过敏功能的间质巨噬细胞群体。 我们将确定导致巨噬细胞基因表达变化的IL-9依赖性途径。最后， 我们将确定Arg 1依赖的代谢途径如何影响巨噬细胞中的内在基因表达。 总之，这些研究将建立对过敏性肺中巨噬细胞功能的详细了解， 确定可以探索治疗价值的途径。